Several lines of evidence suggest that endogenous opioid peptides, enkephalin and dynorphin play important roles in modulating the excitability of the hippocampus. However, the information regarding the regulation of these two opioid peptides has been lacking. The purpose of this project was to examine the molecular mechanisms of the expression of enkephalin and dynorphin in the hippocampus by excitatory amino acids or hormones, such as glucocorticoid. The regulation of glucocorticoid on dynorphin (DYN) gene expression in the hippocampus was examined using rats removed of adrenal glands for 7, 30, and 60 days. Peptide content in adrenalectomized hippocampi were determined with radioimmunoassays and immunocytochemistry. The DYN mRNA was measured with northern blot analysis and in situ hybridization. A time-dependent attenuation of hippocampal levels of dynorphin in adrenalectomized rats was found which was accompanied by a comparable decrease in the abundance of prodynorphin. An in situ hybridization analysis revealed that both the number of positively hybridized cells as well as the number of silver grains per cell in the dentate gyrus were decreased after ADX. Supplementation of dexamethasone immediately after surgery could reverse the peptide and message attenuation resulted by adrenalectomy. Histochemical study by thionin counter stain showed that the dentate granule cell layer appeared to be intact. The decrement of dynorphin expression in this system is proposed to be resulted from the removal of glucocorticoid input and not dentate granule cell loss. In contrast to the change of dynorphin, ADX has not effect on the expression on enkephalin gene in the hippocampus. Our study provides first evidence for a differential susceptibility of these two peptides to the removal of the glucocorticoid in the hippocampus. Since glucocorticoid may serve as a permissive factor in regulating the expression of dynorphin gene in the hippocampus, this provides strong implication for a potential selective glucocorticoid-dependent component in dynorphin gene expression.